Development of parallel forms of a brief smell identification test useful for longitudinal testing.

Although there are numerous brief odor identification tests available for quantifying the ability to smell, none are available in multiple parallel forms that can be longitudinally administered without potential confounding from knowledge of prior test items. Moreover, empirical algorithms for establishing optimal test lengths have not been generally applied. In this study, we employed and compared eight machine learning algorithms to develop a set of four brief parallel smell tests employing items from the University of Pennsylvania Smell Identification Test that optimally differentiated 100 COVID-19 patients from 132 healthy controls. Among the algorithms, linear discriminant analysis (LDA) achieved the best overall performance. The minimum number of odorant test items needed to differentiate smell loss accurately was identified as eight. We validated the sensitivity of the four developed tests, whose means and variances did not differ from one another (Bradley-Blackwood test), by sequential testing an independent group of 32 subjects that included persons with smell dysfunction not due to COVID-19. These eight-item tests clearly differentiated the olfactory compromised subjects from normosmics, with areas under the ROC curve ranging from 0.79 to 0.83. Each test was correlated with the overall UPSIT scores from which they were derived. These brief smell tests can be used separately or sequentially over multiple days in a variety of contexts where longitudinal olfactory testing is needed.

Evaluation of non-Gaussian model-based diffusion-weighted imaging in oral squamous cell carcinoma: comparison with tumour functional information derived from positron-emission tomography.

AIM: To evaluate and compare diffusion-weighted imaging (DWI) parameters derived from a non-Gaussian fitting model and positron-emission tomography (PET) parameters derived from 18F-fluoromisonidazole-PET (FMISO-PET) in patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Primary sites were evaluated prospectively in 18 patients. DWI was performed using six b-values (0-2,500). Diffusion-related parameters of kurtosis value (K), the kurtosis-corrected diffusion coefficient (DK), diffusion heterogeneity (α), distributed diffusion coefficient (DDC), the slow diffusion coefficient (Dslow), and the apparent diffusion coefficient (ADC) were calculated from four diffusion-fitting models. Maximal standardised uptake values (SUVmax), mean standardised uptake values (SUVmean), and the tumour-to-muscle ration (TMR) of the SUV value were calculated for FMISO-PET. Spearman's correlation coefficient was used to evaluate the correlation between each non-Gaussian diffusion model parameters and PET parameter. RESULTS: There was moderate correlation between FMISO-PET SUVmax and Dslow (ρ=-0.45, p=0.06). In addition, there was good correlation between TMRmax and five non-Gaussian diffusion model parameters (K: ρ=0.65, p=0.004, DK: ρ=-0.72, p=0.0008, DDC: ρ=-0.75, p=0.0003, ADC: ρ=-0.74, p=0.0005, and Dslow: ρ= -0.65, p=0.003), and between TMRmean and five non-Gaussian model parameters (K: ρ=0.64, p=0.005, DK: ρ=-0.61, p=0.007, DDC: ρ=-0.63, p=0.005, ADC: ρ=-0.61, p=0.007, and Dslow: ρ=-0.56, p=0.015). CONCLUSION: Non-Gaussian diffusion model parameters can be related to tumour hypoxia.

Evaluation of the compliance with antiemetic guidelines for prevention of chemotherapy-induced nausea and vomiting in patients with hematologic malignancy.

To assess compliance with the Japanese antiemetic guidelines for chemotherapy-induced nausea and vomiting (CINV), the frequencies of CINV occurrence and use of antiemetic rescue medications were examined in patients with hematological malignancy. A total of 40 patients with hematologic malignancy were eligible in this study. This study was performed in the Department of Hematology, Kyushu University Hospital, as a subgroup analysis from a nationwide, multicenter prospective cohort study conducted by the CINV Study Group of Japan. In the patients with hematological malignancy, the guideline compliance rate was 45 %. Five patients (22.7 %) experienced vomiting during the observation period after receiving non-guideline-consistent antiemetic prophylaxis, whereas no patient experienced vomiting after receiving guideline-consistent antiemetic prophylaxis. The study was not sufficiently powered to reach a statistical significance in its frequency of occurrence between the compliance and non-compliance groups. In the entire study period, 8 out of 40 patients required rescue medication, but there was no association between the status of compliance and the antiemetic guidelines. A total of 22 (55.0 %) patients achieved complete response, which was defined as no vomiting and no use of antiemetic rescue medication, during the study period. The rate of compliance with the prophylactic antiemetic treatment guidelines seemed to be low in patients with hematological malignancy, although the status of the guideline compliance did not always influence the antiemetic effects.

Test of the Brink-Axel Hypothesis for the Pygmy Dipole Resonance.

The gamma strength function and level density of 1^{-} states in ^{96}Mo have been extracted from a high-resolution study of the (p[over →], p[over →]^{'}) reaction at 295 MeV and extreme forward angles. By comparison with compound nucleus γ decay experiments, this allows a test of the generalized Brink-Axel hypothesis in the energy region of the pygmy dipole resonance. The Brink-Axel hypothesis is commonly assumed in astrophysical reaction network calculations and states that the gamma strength function in nuclei is independent of the structure of the initial and final state. The present results validate the Brink-Axel hypothesis for ^{96}Mo and provide independent confirmation of the methods used to separate gamma strength function and level density in γ decay experiments.

Increased prevalence of group A streptococcus isolates in streptococcal toxic shock syndrome cases in Japan from 2010 to 2012.

Streptococcal toxic shock syndrome (STSS) is a severe invasive infection characterized by the sudden onset of shock, multi-organ failure, and high mortality. In Japan, appropriate notification measures based on the Infectious Disease Control law are mandatory for cases of STSS caused by ß-haemolytic streptococcus. STSS is mainly caused by group A streptococcus (GAS). Although an average of 60-70 cases of GAS-induced STSS are reported annually, 143 cases were recorded in 2011. To determine the reason behind this marked increase, we characterized the emm genotype of 249 GAS isolates from STSS patients in Japan from 2010 to 2012 and performed antimicrobial susceptibility testing. The predominant genotype was found to be emm1, followed by emm89, emm12, emm28, emm3, and emm90. These six genotypes constituted more than 90% of the STSS isolates. The number of emm1, emm89, emm12, and emm28 isolates increased concomitantly with the increase in the total number of STSS cases. In particular, the number of mefA-positive emm1 isolates has escalated since 2011. Thus, the increase in the incidence of STSS can be attributed to an increase in the number of cases associated with specific genotypes.

Self-Reported Hypersensitivity to Smells: Objective Evidence for Hyposmia, not Hyperosmia.

OBJECTIVE: To compare, using state-of-the-art psychophysical tests, the olfactory function of patients complaining and not complaining of olfactory hypersensitivity. STUDY DESIGN: Retrospective cross-sectional. SETTING: The Smell and Taste Center at the University of Pennsylvania. METHODS: University of Pennsylvania Smell Identification Test (UPSIT) scores were obtained from 148 patients complaining of hyperosmia and 494 patients with no such complaints; detection threshold test scores were obtained from 77 and 483 patients of these respective groups. The effects of subject group, age, and sex on the test scores were assessed using analyses of variance. Categorical variables were evaluated by χ2. Responses to items within a detailed intake questionnaire, for example, the Beck Depression Inventory (BDI-II), were also evaluated. RESULTS: Unexpectedly, those complaining of hyperosmia had lower olfactory test scores than those with no such complaints (respective UPSIT means [95% confidence interval [CIs]] = 27.86 (26.85, 28.87) and 32.19 (31.67, 32.71); P < .001; respective threshold means (log vol/vol) = -4.49 (-4.89, -4.09) and -5.22 (-5.36, -5.06); P < .001). Remarkably, 70.95% of the self-identified hyperosmics exhibited mild to severe microsmia. The hyposmia complainers also exhibited elevated BDI scores (11.02 [9.53, 12.51] vs 7.58 [6.80, 8.34]). CONCLUSION: When objectively tested, many patients who complain of hypersensitivity to odors are actually less sensitive to them. The basis of this phenomenon is unclear. It could reflect the presence of emotionally disturbing altered smell sensations, or one or more comorbidities, such as hypochondria or osmophobia. These findings point to the importance of objective testing of persons with complaints of chemosensory dysfunction and reiterate the inaccuracy of self-reports.

Long-Term Taste and Smell Outcomes After COVID-19.

Importance: Self-report surveys suggest that long-lasting taste deficits may occur after SARS-CoV-2 infection, influencing nutrition, safety, and quality of life. However, self-reports of taste dysfunction are inaccurate, commonly reflecting deficits due to olfactory not taste system pathology; hence, quantitative testing is needed to verify the association of post-COVID-19 condition with taste function. Objective: To use well-validated self-administered psychophysical tests to investigate the association of COVID-19 with long-term outcomes in taste and smell function. Design, Setting, and Participants: This nationwide cross-sectional study included individuals with and without a prior history of COVID-19 recruited from February 2020 to August 2023 from a social media website (Reddit) and bulletin board advertisements. In the COVID-19 cohort, there was a mean of 395 days (95% CI, 363-425 days) between diagnosis and testing. Exposure: History of COVID-19. Main Outcomes and Measures: The 53-item Waterless Empirical Taste Test (WETT) and 40-item University of Pennsylvania Smell Identification Test (UPSIT) were used to assess taste and smell function. Total WETT and UPSIT scores and WETT subtest scores of sucrose, citric acid, sodium chloride, caffeine, and monosodium glutamate were assessed for groups with and without a COVID-19 history. The association of COVID-19 with taste and smell outcomes was assessed using analysis of covariance, χ2, and Fisher exact probability tests. Results: Tests were completed by 340 individuals with prior COVID-19 (128 males [37.6%] and 212 females [62.4%]; mean [SD] age, 39.04 [14.35] years) and 434 individuals with no such history (154 males [35.5%] and 280 females [64.5%]; mean (SD) age, 39.99 [15.61] years). Taste scores did not differ between individuals with and without previous COVID-19 (total WETT age- and sex-adjusted mean score, 33.41 [95% CI, 32.37-34.45] vs 33.46 [95% CI, 32.54-34.38]; P = .94). In contrast, UPSIT scores were lower in the group with previous COVID-19 than the group without previous COVID-19 (mean score, 34.39 [95% CI, 33.86-34.92] vs 35.86 [95% CI, 35.39-36.33]; P < .001]); 103 individuals with prior COVID-19 (30.3%) and 91 individuals without prior COVID-19 (21.0%) had some degree of dysfunction (odds ratio, 1.64 [95% CI, 1.18-2.27]). The SARS-CoV-2 variant present at the time of infection was associated with smell outcomes; individuals with original untyped and Alpha variant infections exhibited more loss than those with other variant infections; for example, total to severe loss occurred in 10 of 42 individuals with Alpha variant infections (23.8%) and 7 of 52 individuals with original variant infections (13.5%) compared with 12 of 434 individuals with no COVID-19 history (2.8%) (P < .001 for all). Conclusions and Relevance: In this study, taste dysfunction as measured objectively was absent 1 year after exposure to COVID-19 while some smell loss remained in nearly one-third of individuals with this exposure, likely explaining taste complaints of many individuals with post-COVID-19 condition. Infection with earlier untyped and Alpha variants was associated with the greatest degree of smell loss.

The 8-item NHANES pocket smell test®: Normative data.

This study provides normative data useful for interpreting scores from the Pocket Smell Test® (PST®), a brief "scratch & sniff" neuropsychological olfactory screening test comprised of 8 items from the 40-item University of Pennsylvania Smell Identification Test (UPSIT®). We combined 3,485 PST® scores from the 2013 to 2014 National Health and Nutrition Survey (NHANES) of persons 40 years of age and older with equivalent PST® items extracted from an UPSIT® database of 3,900 persons ranging in age from 5 to 99 years. Decade-related age- and gender-adjusted percentile normative data were established across the entire age spectrum. Cut-points for defining clinically useful categories of anosmia, probable microsmia, and normosmia were determined using receiver operating characteristic (ROC) curve analyses. An age-related decline in test scores was evident for both sexes after the age of 40 years, with women outperforming men. Based on the ROC analyses, subjects scoring 3 or less (AUC = 0.81) defines anosmia. Regardless of sex, a score of 7 or 8 on the N-PST® signifies normal function (AUC of 0.71). Probable microsmia is classified as scores extending from 3 to 6. These data provide an accurate means for interpreting PST® scores within a number of clinical and applied settings.

Separation of pygmy dipole and M1 resonances in 90Zr by a high-resolution inelastic proton scattering near 0°.

A high-resolution measurement of inelastic proton scattering off (90)Zr near 0° was performed at 295 MeV with a focus on a pronounced strength previously reported in the low-energy tail of giant dipole resonance. A forest of fine structure was observed in the excitation energy region 7-12 MeV. A multipole decomposition analysis of the angular distribution for the forest was carried out using the ECIS95 distorted-wave Born approximation code with the Hartree-Fock plus random-phase approximation model of E1 and M1 transition densities and inclusion of E1 Coulomb excitation. The analysis separated pygmy dipole and M1 resonances in the forest at E(PDR)=9.15±0.18 MeV with Γ(PDR)=2.91±0.64 MeV and at E(M1)=9.53±0.06 MeV with Γ(M1)=2.70±0.17 MeV in the Lorentzian function, respectively. The B(E1)↑ value for pygmy dipole resonance over 7-11 MeV is 0.75±0.08 e(2)fm(2), which corresponds to 2.1±0.2% of the Thomas-Reiche-Kuhn sum rule.

Characteristics of gut microbiome, organic acid profiles and viral antibody indexes of healthy Japanese with live Lacticaseibacillus detected in stool.

To estimate the health-promoting effects of Lacticaseibacillus paracasei (previously Lactobacillus casei) strain Shirota (LcS) that reached the lower gastrointestinal tract alive, we investigated the characteristics of gut microbiome, organic acid profiles, defecatory symptoms and serum viral antibody indexes of healthy Japanese adults between the group in whom live LcS was detected or not from stool. The ß-diversity index of the gut microbiome constituted a significant difference between the live-LcS-detected-group (LLD) and the live-LcS-not-detected-group (LLnD). In the LLD, the Bifidobacteriaceae, Lactobacillaceae, and Coriobacteriaceae counts were significantly higher, and the succinate concentration was significantly lower than that in the LLnD. The serum herpes simplex virus (HSV) immunoglobulin (Ig)M antibody index in the LLD tended to be lower than that of the LLnD in HSV IgG-positive subjects. Of the LLD, those in the fermented milk products containing LcS (FML)-high-frequency-group (FML-HF) and those in the FML-low-frequency-group (FML-LF) had different gut microbiome and organic acid profiles. However, the pattern of differences between FML-HF and FML-LF was dissimilar those between LLD and LLnD. In contrast, among subjects with FML-LF, those in the group with LLD in stool (LF-LLD) and those in the LLnD in stool (LF-LLnD) showed a similar pattern of differences in their gut microbiome and organic acid profiles as those in the LLnD and LLD. The LLD and LF-LLD commonly had lower caloric and carbohydrate intakes from the diet than their respective control groups. In this study, we found that the presence of live LcS in stool is associated with a healthy gut environment and inhibition of the reactivation of latently infected viruses in the host. However, these health-promoting effects on the host were not related to the frequency of FML intake. Furthermore, dysbiosis of the gut microbiome and diet including caloric intake was related to the viability of ingested LcS in the gut.

Role of probiotic in preventing acute diarrhoea in children: a community-based, randomized, double-blind placebo-controlled field trial in an urban slum.

Acute diarrhoea remains a major public health challenge in developing countries. We examined the role of a probiotic in the prevention of acute diarrhoea to discover if there was an effect directed towards a specific aetiology. A double-blind, randomized, controlled field trial involving 3758 children aged 1-5 years was conducted in an urban slum community in Kolkata, India. Participants were given either a probiotic drink containing Lactobacillus casei strain Shirota or a nutrient drink daily for 12 weeks. They were followed up for another 12 weeks. The primary outcome of this study was the occurrence of first episodes of diarrhoea. We assessed this during 12 weeks of intake of study agent and also for 12 weeks of follow-up. There were 608 subjects with diarrhoea in the probiotic group and 674 subjects in the nutrient group during the study period of 24 weeks. The level of protective efficacy for the probiotic was 14% (95% confidence interval 4-23, P<0·01 in adjusted model). The reduced occurrence of acute diarrhoea in the probiotic group compared to nutrient group was not associated with any specific aetiology. No adverse event was observed in children of either probiotic or nutrient groups. The study suggests that daily intake of a probiotic drink can play a role in prevention of acute diarrhoea in young children in a community setting of a developing country.

Prevalence and reversibility of smell dysfunction measured psychophysically in a cohort of COVID-19 patients.

BACKGROUND: Considerable evidence suggests that smell dysfunction is common in coronavirus disease-2019 (COVID-19). Unfortunately, extant data on prevalence and reversibility over time are highly variable, coming mainly from self-report surveys prone to multiple biases. Thus, validated psychophysical olfactory testing is sorely needed to establish such parameters. METHODS: One hundred severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-positive patients were administered the 40-item University of Pennsylvania Smell Identification Test (UPSIT) in the hospital near the end of the acute phase of the disease. Eighty-two were retested 1 or 4 weeks later at home. The data were analyzed using analysis of variance and mixed-effect regression models. RESULTS: Initial UPSIT scores were indicative of severe microsmia, with 96% exhibiting measurable dysfunction; 18% were anosmic. The scores improved upon retest (initial test: mean, 21.97; 95% confidence interval [CI], 20.84-23.09; retest: mean, 31.13; 95% CI, 30.16-32.10; p < 0.0001); no patient remained anosmic. After 5 weeks from COVID-19 symptom onset, the test scores of 63% of the retested patients were normal. However, the mean UPSIT score at that time continued to remain below that of age- and sex-matched healthy controls (p < 0.001). Such scores were related to time since symptom onset, sex, and age. CONCLUSION: Smell loss was extremely common in the acute phase of a cohort of 100 COVID-19 patients when objectively measured. About one third of cases continued to exhibit dysfunction 6 to 8 weeks after symptom onset. These findings have direct implications for the use of olfactory testing in identifying SARS-CoV-2 carriers and for counseling such individuals with regard to their smell dysfunction and its reversibility.

Smell dysfunction: a biomarker for COVID-19.

BACKGROUND: Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), is responsible for the largest pandemic since the 1918 influenza A virus subtype H1N1 influenza outbreak. The symptoms presently recognized by the World Health Organization are cough, fever, tiredness, and difficulty breathing. Patient-reported smell and taste loss has been associated with COVID-19 infection, yet no empirical olfactory testing on a cohort of COVID-19 patients has been performed. METHODS: The University of Pennsylvania Smell Identification Test (UPSIT), a well-validated 40-odorant test, was administered to 60 confirmed COVID-19 inpatients and 60 age- and sex-matched controls to assess the magnitude and frequency of their olfactory dysfunction. A mixed effects analysis of variance determined whether meaningful differences in test scores existed between the 2 groups and if the test scores were differentially influenced by sex. RESULTS: Fifty-nine (98%) of the 60 patients exhibited some smell dysfunction (mean [95% CI] UPSIT score: 20.98 [19.47, 22.48]; controls: 34.10 [33.31, 34.88]; p < 0.0001). Thirty-five of the 60 patients (58%) were either anosmic (15/60; 25%) or severely microsmic (20/60; 33%); 16 exhibited moderate microsmia (16/60; 27%), 8 mild microsmia (8/60; 13%), and 1 normosmia (1/60; 2%). Deficits were evident for all 40 UPSIT odorants. No meaningful relationships between the test scores and sex, disease severity, or comorbidities were found. CONCLUSION: Quantitative smell testing demonstrates that decreased smell function, but not always anosmia, is a major marker for SARS-CoV-2 infection and suggests the possibility that smell testing may help, in some cases, to identify COVID-19 patients in need of early treatment or quarantine.

Disseminated tuberculosis following second unrelated cord blood transplantation for acute myelogenous leukemia.

Here we report the case of a 43-year-old Japanese woman with acute myelogenous leukemia who underwent 2 unrelated cord blood transplantations (UCBT), terminating in fatal disseminated tuberculosis (TB). The patient did not achieve remission despite intensive chemotherapy, and subsequently underwent UCBT with a standard conditioning regimen. However, engraftment was not achieved. Fifty days after the first UCBT, the patient underwent a second UCBT with a reduced-intensity conditioning regimen. She developed a pre-engraftment immune reaction, which responded well to prednisolone, and engraftment was documented. However, 50 days after the second UCBT, the patient presented with high fever and developed pneumonia despite antibiotic and antifungal treatments. Thereafter, Mycobacterium tuberculosis was detected in blood cultures and specimens of bronchoalveolar lavage, thus indicating disseminated TB. Despite anti-tuberculous treatment, she died on day 85. TB should always be considered as a possible diagnosis when treating febrile immunocompromised patients.

Experimental study of fast-neutron production and moderation for accelerator-based BNCT system.

This work aims to study the fast-neutron production and moderation for the development of a compact accelerator-based multi-port Boron Neutron Capture Therapy (AB-mBNCT) system. An initial energy distribution and the efficiency of a test moderator assembly (TMA) for fast neutrons from a tungsten (W) target bombarded with a 53 MeV proton beam were measured using organic scintillators. The experimental results were reproduced with reasonable accuracy by simulations using the PHITS code. This paper will discuss about the experimental outcome and the related benchmark calculations by PHITS code.

Association of life habits and fermented milk intake with stool frequency, defecatory symptoms and intestinal microbiota in healthy Japanese adults.

Few studies have examined the effects of smoking habit, the frequency of alcohol drinking, exercise, and fermented milk consumption on defecatory symptoms and gut microbiota composition, and particularly their interactive effects. We examined the effect of these lifestyle factors on bowel movements and gut microbiota composition in 366 healthy Japanese adults by analysis of covariance. Smoking did not affect defecatory symptoms but was negatively correlated with total bacteria and Enterococcus counts. Drinking frequency was significantly positively correlated with a feeling of incomplete evacuation and counts of the Bacteroides fragilis group and Acidaminococcus groups. Exercise frequency tended to be negatively correlated with the Bristol Stool Form Scale score and was significantly negatively correlated with the counts of Enterobacteriaceae and positively correlated with the Prevotella counts in the faeces. The frequency of fermented milk consumption was not significant but tended to be positively correlated with stool frequency. The frequency of fermented milk consumption was significantly positively correlated with the counts of the Atopobium cluster, Eubacterium cylindroides group, Acidaminococcus group, Clostridium ramosum subgroup, and Lactobacillus in the faeces. The frequency of consumption of probiotic Lactobacillus casei-containing fermented milk was significantly positively correlated with stool frequency. The counts of probiotic Lactobacillus casei in the stool was positively correlated with the counts of Bifidobacterium and total Lactobacillus. These results suggest that smoking, alcohol drinking, exercise, and consumption of fermented milk, particularly containing probiotic L. casei, differently affect bowel movements and gut microbiota composition in healthy Japanese adults.

Omission of lymphadenectomy is possible for low-risk corpus cancer.

AIM: The objective of this study is to ascertain whether omission of lymphadenectomy is possible when endometrial cancer is considered low-risk based on intraoperative pathologic indicators. PATIENT AND METHODS: A total of 128 patients were deemed to be low-risk based on intraoperative evaluation, including frozen-section determination of grade and myometrial invasion. We divided these 128 patients into 2 groups, the total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) with lymphadenectomy (LA group, n=68) and the TAH-BSO without lymphadenectomy (non-LA group, n=60) group. The only adjuvant treatment used was chemotherapy, and the decision to use chemotherapy was based on stage, grade, or lymphovascular space involvement. A retrospective review of the medical records was performed, and disease-free survival (DFS), overall survival (OS), operative time, estimated blood loss during operation, percentage of transfusion requirement, incidence of post-operative leg lymphedema and post-operative deep vein thrombosis were evaluated. RESULTS: The 5-year DFS and OS rates were 95.6% and 98.5% in the LA group, and 98.3% and 98.3% in the non-LA group, respectively, and were not significantly different. In the LA group, pelvic lymph node metastasis was observed in only 1 case. In the LA group, blood loss during operation, percentage of transfusion requirement and the incidence of post-operative leg lymphedema were significantly higher than those in the non-LA group. CONCLUSION: Lymphadenectomy did not provide a significant survival advantage in the patients with low-risk corpus cancer. Additionally, some peri- and post-operative morbidities and complications were increased by the addition of lymphadenectomy. The present findings suggest that lymphadenectomy should be limited for low-risk corpus cancer.

ICI 164,384, a pure antagonist of estrogen-stimulated MCF-7 cell proliferation and invasiveness.

Estrogen is known to stimulate the proliferation and basement membrane invasiveness of the MCF-7 human breast cancer cell line. We have compared the new steroidal antiestrogen ICI 164,384, the triphenylethylene 4-hydroxytamoxifen (OHT), and the benzothiophene LY 117018, for their effects on the proliferation and invasiveness of the MCF-7 cell line and its antiestrogen-resistant variant LY-2. While all three antiestrogens blocked the proliferative effects of 17 beta-estradiol on MCF-7 cells, OHT and LY 117018, but not ICI 164,384 stimulated their proliferation in the absence of estrogen. The proliferative effects of OHT and LY 117018 were blocked by ICI 164,384. Basement membrane invasiveness of MCF-7 cells was stimulated by 17 beta-estradiol and OHT, but not LY 117018 or ICI 164,384. Both ICI 164,384 and LY 117018 were able to block the invasiveness induced by either 17 beta-estradiol or OHT. The LY-2 antiestrogen-resistant variant of the MCF-7 cell line showed increased basal proliferation, and responded only slightly to estrogen. ICI 164,384, but not OHT or LY 117018 antagonized the effects of 17 beta-estradiol, but did not reduce proliferation below control levels. The LY-2 line was not resistant to the antiestrogenic effects of LY 117018 or ICI 164,384 on invasiveness, and was stimulated by LY 117018 for this parameter. Thus, ICI 164,384 is a pure antiestrogen for MCF-7 cell proliferation and invasiveness, and may offer clinical advantage over nonsteroidal antiestrogens which can stimulate these activities in tumor models in vitro.

Supernatants of acquired immunodeficiency syndrome-related Kaposi's sarcoma cells induce endothelial cell chemotaxis and invasiveness.

Kaposi's sarcoma (KS) in general, and acquired immunodeficiency syndrome-related KS (AIDS-KS) in particular, is a highly invasive and intensely angiogenic neoplasm of unknown cellular origin. We have recently established AIDS-KS cells in long term culture and reported the development of KS-like lesions in nude mice inoculated with these cells. Here, we have examined the in vitro invasiveness of basement membrane by AIDS-KS cells, as well as the effect(s) of their supernatants on the migration and invasiveness of human vascular endothelial cells. AIDS-KS cells were highly invasive in the Boyden chamber invasion assay and formed invasive, branching colonies in a 3-dimensional gel (Matrigel). Normal endothelial cells form tube-like structures on Matrigel. AIDS-KS cell-conditioned media induced endothelial cells to form invasive clusters in addition to tubes. KS-cell-conditioned media, when placed in the lower compartment of the Boyden chamber, stimulated the migration of human and bovine vascular endothelial cells across filters coated with either small amounts of collagen IV (chemotaxis) or a Matrigel barrier (invasion). Basic fibroblast growth factor could also induce endothelial cell chemotaxis and invasion in these assays. However, when antibodies to basic fibroblast growth factor were used the invasive activity induced by the AIDS-KS-cell-conditioned media was only marginally inhibited, suggesting that the large quantities of basic fibroblast growth factor-like material released by the AIDS-KS cells are not the main mediators of this effect. Specific inhibitors of laminin and collagenase IV action, which represent critical determinants of basement membrane invasion, blocked the invasiveness of the AIDS-KS cell-activated endothelial cells in these assays. These data indicate that KS cells appear to be of smooth muscle origin but secrete a potent inducer of endothelial cell chemotaxis and invasiveness which could be responsible for angiogenesis and the resulting highly vascularized lesions. These assays appear to be a model to study the invasive spread and angiogenic capacity of human AIDS-related KS and should prove useful in the identification of molecular mediators and potential inhibitors of neoplastic neovascularization.